Response to First Course of Intensified Immunosuppression in Genetically-Stratified Steroid Resistant Nephrotic Syndrome

Anna Mason, Ethan S Sen, Agnieszka Bierzynska, Elizabeth Colby, Maryam Afzal, Guillaume Dorval, Ania Koziell, Maggie Williams, Olivia Boyer, Gavin I Welsh, Moin Saleem*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Background and objectives Intensified immunosuppression in steroid-resistant nephrotic syndrome is broadly applied, with disparate outcomes. This review of patients from the United Kingdom National Study of Nephrotic Syndrome cohort aimed to improve disease stratification by determining, in comprehensively genetically screened patients with steroid-resistant nephrotic syndrome, if there is an association between response to initial intensified immunosuppression and disease progression and/or post-transplant recurrence. Design, setting, participants, & measurements Pediatric patients with steroid-resistant nephrotic syndrome were recruited via the UK National Registry of Rare Kidney Diseases. All patients were whole-genome sequenced, whole-exome sequenced, or steroid-resistant nephrotic syndrome gene-panel sequenced. Complete response or partial response within 6 months of starting intensified immunosuppression was ascertained using laboratory data. Response to intensified immunosuppression and outcomes were analyzed according to genetic testing results, pattern of steroid resistance, and first biopsy findings. Results Of 271 patients, 178 (92 males, median onset age 4.7 years) received intensified immunosuppression with response available. A total of 4% of patients with monogenic disease showed complete response, compared with 25% of genetic-testing-negative patients (P=0.02). None of the former recurred post-transplantation. In genetic-testing-negative patients, 97% with complete response to first intensified immunosuppression did not progress, whereas 44% of nonresponders developed kidney failure with 73% recurrence post-transplant. Secondary steroid resistance had a higher complete response rate than primary/presumed resistance (43% versus 23%; P=0.001). The highest complete response rate in secondary steroid resistance was to rituximab (64%). Biopsy results showed no correlation with intensified immunosuppression response or outcome. Conclusions Patients with monogenic steroid-resistant nephrotic syndrome had a poor therapeutic response and no post-transplant recurrence. In genetic-testing-negative patients, there was an association between response to first intensified immunosuppression and long-term outcome. Patients with complete response rarely progressed to kidney failure, whereas nonresponders had poor kidney survival and a high post-transplant recurrence rate. Patients with secondary steroid resistance were more likely to respond, particularly to rituximab.
Original languageEnglish
Article numberCJN.13371019
JournalClinical Journal of the American Society of Nephrology
Early online date21 Apr 2020
DOIs
Publication statusE-pub ahead of print - 21 Apr 2020

Keywords

  • nephrotic syndrome
  • pediatric nephrology
  • Cohort Studies
  • Registries
  • Disease Progression
  • Biopsy
  • Renal Insufficiency
  • Genetic Testing
  • Base Sequence
  • immunosuppression
  • Radar
  • Exome
  • Rituximab
  • transplant outcomes
  • progression of renal failure

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